Obesity is increasing prevalent, and over 2.8 million people die each year as a result of being overweight or obese. Consequently, identifying factors to prevent weight gain and obesity is extremely important to public health. The overall goal of this research program is to understand central regulation of eating behavior in ways that can be applied to reduce obesity. The objective of this particular application is to use functional magnetic resonance imaging (fMRI) to understand the effects of high reward foods, including the ingestion of different types of sugar, on appetite and its central regulation in humans. We previously found differential neuroendocrine and appetite responses to ingestion of two simple sugars, glucose and fructose, in normal- weight adults. The ingestion of fructose reduced cerebral blood flow (CBF), a marker of neuronal activity, in the hypothalamus (appetite region) less than ingestion of glucose. Fructose also stimulated levels of two potential satiety hormones, insulin and GLP-1, less than glucose and failed to induce the satiety that was observed after glucose ingestion. These preliminary studies provide mechanistic insights into epidemiological evidence linking fructose consumption to overeating and obesity and provide strong rationale for the work proposed here. The current proposal will use a combination of arterial spin labeling and fMRI-blood-oxygen- level dependent (BOLD) techniques to test the following hypotheses: (1) fructose compared to glucose ingestion will result in greater food-cue reactivity in central appetite and reward pathways and increased feeding behavior; (2) sucrose (50% glucose and 50% fructose) will produce brain reward and hormone responses that are similar to pure fructose and greater than pure glucose; (3) ingestion of the non-caloric sweetener, sucralose, will result in increased activity in central appetite and reward regions and will result in a heightened appetitive response to food cues. The proposed research is significant because it will determine the effects of caloric and non-caloric sweeteners on the neurobiological pathways underlying appetite and obesity. Findings from these studies will provide mechanistic insights and practical information that can be used to help develop more effective dietary strategies for weight loss and obesity prevention.